Scientists reveal genetic ‘signatures’ left by cigarette smoke

Researchers first found a link between smoking and lung cancer back in the 1950s. But science has moved on drastically since then. With better designed studies and more sophisticated techniques, our understanding of the harms caused by tobacco has significantly improved.

For starters, it’s not just lung cancer that smoking causes – the habit is now linked with at least 14 types of cancer, including pancreatic, oesophageal and bladder cancers.

But the big question is: how precisely does cigarette smoking harm the DNA in our cells to such a devastating degree that it causes cancer?

Now a detailed new study, led by scientists at the Wellcome Trust Sanger Institute and published in the journal Science, is beginning to reveal the details. And it seems that the situation is more complex, and more sinister, than previously appreciated.

Strikingly, it seems that different tissues of the body display different hallmarks of smoking damage, underlining once again just how devastating smoking can be.

Mixing up the alphabet

More than a quarter of all cancer deaths in the UK are down to smoking. And the habit accounts for nearly a fifth of all cancer cases, alongside causing a whole host of other diseases and health problems.

The reason puffing on cigarettes is so harmful is because tobacco smoke is jam-packed with chemicals, of which more than 70 may cause cancer. These make their way from the lungs into the blood, spreading around the body to our various organs and wreaking havoc wherever they go.

You can find hundreds, if not thousands of different genetic faults in tumours.

– Professor David Phillips, Cancer Research UK

It’s thought that many of these chemicals raise the risk of cancer by directly damaging our DNA code. If left unrepaired, this damage can sometimes cause the cell to grow out of control, which may lead to cancer.

“You can find hundreds, if not thousands of different genetic faults in tumours,” says Professor David Phillips, a Cancer Research UK scientist and one of the researchers who helped lead the new study. “Together these give you a record of what the tumour-causing cells have been exposed to over a long period, as they accumulate over time.”

And these faults come in a variety of different patterns, depending on how the string of ‘letters’ in the DNA code has been jumbled. These distinct patterns are known as ‘signatures’, and they represent the focus of the latest study.

“Some of these ‘signatures’ can be attributed to a particular process in the cell, or a certain carcinogen from the environment,” Phillips says. “But many are of unknown origin.”

A familiar sign

In their latest study, the Sanger team looked at DNA samples from a range of tumours spanning 2500 smokers and more than 1000 people who had never smoked. By comparing smokers and non-smokers, the team hoped to find the genetic ‘signatures’ in cancer that are linked with smoking.

They found that only those tissues directly exposed to cigarette smoke, like the lungs, experience a direct assault to their DNA. In other tissues it seems the harmful substances in cigarette smoke are accelerating natural processes in the cell that can cause DNA damage.

While the researchers found a number of distinct ‘signatures’ across the cancer types, just five were found in higher levels in tumour samples from smokers. This suggests that there are at least five distinct ways that smoking can damage DNA.

One of the signatures, number 4, particularly piqued the interest of the researchers. This was only found in cancers linked to smoking, and was mostly limited to areas of the body that come into direct contact with cigarette smoke, including the lungs and voice box. It also looked very similar to the ‘signature’ scientists see if they expose cells in a dish to a particular carcinogen found in tobacco smoke.

“This ‘smoking signature’ is a close match to the one caused by the carcinogen benzo[a]pyrene,” says Phillips.

“It’s found in high levels in smokers, but you don’t often see it in lung cancer samples from non-smokers, nor was it found in tissues that aren’t directly exposed to tobacco smoke.”

In quite a striking contrast, another ‘signature’ – number 5 – was found in all cancers, rather than just those linked with smoking. And it was also present in non-smokers. The signature was still found at higher levels in samples from those who smoked though, suggesting smoking accelerates this damage, but the team believe a different mechanism is causing it.

In fact, this signature appears to be the result of an unknown process within cells that naturally causes genetic faults to build up throughout a person’s life.

“We don’t know what this exact process is, but it appears to be causing an accumulation of genetic mistakes in a steady, clock-like rate over time,” explains Phillips.

“And somehow, smoking seems to be speeding this clock up. Smokers have more of these particular genetic faults than you would expect for their age.”

Written in the cells

What seems to be the emerging picture here is that the genetic damage caused by smoking is a complex mixture of direct harm to cells that are exposed to tobacco smoke itself, and indirect harm in those that aren’t.

“Even though we know that tobacco carcinogens travel throughout the body to other tissues, it appears that they aren’t directly damaging the DNA in these areas.

“Instead they’re activating another process that accelerates the formation of genetic mistakes.”

And the burden of being directly exposed to cigarette smoke became even clearer when the researchers married up smoking rates with the numbers of genetic faults found in various cancers.

Working backwards, the researchers found that smoking a pack of cigarettes a day could cause roughly 150 new DNA mistakes to appear in normal lung cells each year. And other tissues of the respiratory system – the larynx, pharynx and mouth – weren’t far behind, racking up 97, 39 and 23 each year, respectively.

But while the research seems to be providing some answers, it has also left lingering questions.

“Cervical cancers showed a range of signatures, but we couldn’t distinguish between smokers and non-smokers,” says Phillips.

“Many studies have shown that smoking is a risk factor for cervical cancer, but whether it’s independent of the human papillomavirus – which some argue underlies all cervical cancers – is up for debate.”

Clearing the haze

Clearly there is more work to be done to unravel the true spectrum of genetic harm caused by smoking.

But at the very least this research reinforces the severity of the situation at hand, highlighting the fact that smoking can both directly and indirectly damage DNA.

According to Dr Nicholas McGranahan, a Francis Crick Institute scientist who was not involved in the research, this discovery is key.

“As has long been established, smoking clearly plays a role in triggering the development of tumours by directly causing DNA damage,” he says.

This research isn’t telling us anything new about the fact that tobacco smoke causes cancer, but it’s giving us insight into how.

– Professor David Phillips

“But this work also highlights the role that smoking can have in activating additional processes which may make the tumour even more difficult to treat.”

That’s why this research is so important. Because understanding more about how risk factors cause cancer can help scientists develop better ways to tackle them, or develop strategies to reduce people’s risk.

While this research may be a stark reminder of the devastation caused by smoking, it’s important to stress that it’s never too late to quit: those who stop smoking show an improved life expectancy compared with those who continue to smoke.

“This research isn’t telling us anything new about the fact that tobacco smoke causes cancer, but it’s giving us insight into how,” says Phillips.

“And it’s telling us that cigarette smoke is not doing the same thing in different tissues, highlighting the complexity of its effects.”

If you’re a smoker, there’s lots of free support available to give you the best possible chance of kicking the habit. And if you’d like to help our campaign to keep Stop Smoking Services free, you can find out how to take action here.

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I know what smoking can do, with both parents dying of smoking related heart disease (father at 60), and parents in law of emphysema (from second hand smoke) and lung cancer. On my mother’s side both her brother and sister smoked and suffered heart problems. Many people insist smoke will not harm me (they do not know my medical history!) and smoke near me even though I have asked politely for them not to, a neighbour has regularly gone out of her way to come out and smoke when I dare to go into our own garden ever since they moved in and claims when I have bronchitis I have a “fake cough”!). Incidentally she smoked all the way through her last pregnancy, several times a day, the baby had some medical issues when born, but as we do not get on (no surprise there), we do not know the extent of the problems. I suffered numerous blood clots in both lungs 3-4 years ago, and am left with chronic bronchitis, so if I catch a cold, I end up with bronchitis, for several months at a time. Even one person berated me with comments like second hand smoke does not exist and that the smoke exhaled is only water vapour. Yes, he is a smoker and not a vaper, and meant cigarette smoke! For me, even the vapour from e-cigarettes affect my breathing. It appears that smokers and vapers feel it is their right to pollute everybody and everywhere is more important than other people’s right to breathe. My husband has a throat clearing problem like his mother, and we wondered if it was because his father smoked and his mother ran a pub many years ago, which is probably why she ended up with emphysema.

Hi Julia and Jan.
Thanks very much for reading and taking the time to comment.
We’re sorry to hear about your family members.
Smoking damages DNA inside cells. And while it can also damage eggs, sperm, and affect babies in the womb, it isn’t clear whether these changes make children more likely to develop cancer in later life. But it’s important to be aware that smoking during pregnancy is harmful to the growing baby http://www.nhs.uk/conditions/pregnancy-and-baby/pages/smoking-pregnant.aspx.
People who are exposed to second-hand smoke are at a higher risk of some types of cancer. It isn’t clear whether the age at which the exposure occurs is important – though we do know that the more someone is exposed to, the bigger the increase in their risk of cancer.
Second-hand smoke is also linked with lots of other diseases. And among children it has been linked to around 165,000 new cases of diseases like asthma and respiratory infections in the UK each year. You can read more about this on our website http://www.cancerresearchuk.org/about-cancer/causes-of-cancer/smoking-and-cancer/passive-smoking.
Because we’re exposed to lots of different things in life, it’s usually very difficult to be certain of the exact cause of an individual person’s cancer. And there are many things that affect the risk of developing cancer, which involve a combination of our genes, our environment and our lifestyles.
Best wishes,
Justine, Cancer Research UK

My sister aged 80 has just been diagnosed with liver and oesophogal cancer. some years ago she had a kidney removed and also bladder cancer, but not of the most malignant type. she was told that it was because our mother smoked.
Is it true that a smoker can pass genetic damage to her children directly?

Has there been a study of cancers in patients who were exposed to cigarette smoke as children but who have not smoked in their adult lives? My father was a heavy smoker, he died of COPD at age 64 when I was 20.

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